An autism brain signature?

A set of molecular pathways abnormally expressed in the brains of autism patients may provide new therapeutic targets

By Megan Scudellari | May 25, 2011

A genome-wide analysis of the RNA in the brains of individuals with autism reveals consistent patterns of abnormal gene expression and implicates several molecular pathways in the pathology of autism.

The autism awareness ribbon is designed to reflect the complexity and diversity of autism. Scientists now believe common molecular pathways may underlie the disease. Credit: linkurl:Wikimedia Commons;http://commons.wikimedia.org/wiki/File:Autism_Awareness_Ribbon.png

The research, published today in linkurl:Nature,;http://www.nature.com/nature suggests that shared molecular pathways underlie autism, a notoriously heterogeneous disease, which may point the way to biomarkers and therapeutic targets for the disease.
"Here, using an unbiased genome-wide scanning method looking at the RNA rather than the DNA, we clearly identify these two major processes going on that are common to a majority of autism brains," said senior author linkurl:Daniel Geschwind;http://geschwindlab.neurology.ucla.edu/ of the University of California, Los Angeles.
"This is really well done study, with appropriate sample sizes and well thought through," said linkurl:Karoly Mirnics,;http://mirnicslab.vanderbilt.edu/mirnicslab/ a neuroscientist at Vanderbilt University who was not involved in the research. "We need more of these kinds of rigorous studies."
Instead of comparing DNA sequences of people with autism against normal controls, as done in many genome-wide association studies, Geschwind and colleagues decided to look at the mRNA, or transcriptome, of individuals with autism to identify any abnormalities in gene expression.
They compared brain tissue samples from 19 autism patients with 17 controls and measured the abundance of mRNA in the cerebellum and cerebral cortex. In total, 444 genes were differentially expression in the autism cortex samples. And there was a surprising pattern: In normal brains, gene expression in frontal lobe varies significantly from that in the temporal lobe due to the different functions of the two regions of the brain. But in autism brains, the levels of gene expression between the two lobes were homogenized, as if the two regions did not have disparate functions.
"The paper implies that the different brain regions in autism are not specialized as they should be," said Mirnics, who wrote an accompanying News & Views article in Nature. "It very well might be the result of impaired development." This pattern of abnormal gene expression was shared by more than two-thirds of the autism patients, suggesting that the altered molecular pathways are common in brains with autism, an important and debated point in autism research. Because autism cases vary widely in terms of phenotype and only a few genes have been implicated across the whole spectrum of autism disorders, researchers have suspected that there are no common causes of the disease, making it extremely hard to develop widely applicable autism therapies.
"If you have 100 cases of autism, we used to think there were 110 mutations," said Geschwind. "This is now telling us there are common patterns."
To further explore the differences, the team focused on two networks where altered gene expression of one or a few genes appeared to be driving the abnormal expression of a group of interacting genes. One of these was A2BP1, a master gene splicer. The team found that A2BP1 was downregulated in brains with autism, and resulted in the abnormal splicing of genes involved in synaptic function. A second network included multiple astrocyte markers, ADFP and IFITM2, whose upregulated expression affected immune and inflammatory genes.
Using a technique called network analysis to organize the data, the team compared their findings to genome-wide association studies of non-psychiatric disease, and concluded that the A2BP1 network of affected genes is genetically associated with autism and could even be causal, while the over expression of immune genes was not. Together, the two processes show a high degree of correlation, but "the immune response is probably secondary" to synaptic dysfunction or caused by environmental factors, said Geschwind.
It will take time to understand how these molecular pathways are connected, but the identification of common, abnormally expressed molecular pathways in this heterogeneous disease provides hope that common treatments can be developed for individuals all along the autism spectrum. "It provides a springboard for focused studies that should get us more quickly to therapies," said Geschwind.
Voineagu, I., et al., "Transcriptomic analysis of autistic brain reveals convergent molecular pathology," Nature, doi: 10.1038/nature10110, 2011.**__Related stories:__***linkurl:DNA-RNA mismatch;http://www.the-scientist.com/news/display/58176/ [19th May 2011] *linkurl:New autism loci discovered;http://www.the-scientist.com/blog/display/55186/ [12th November 2008] *linkurl:Copy number linked to autism;http://www.the-scientist.com/news/display/52940/ [15th March 2007]

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Doctors should probably be warning expectant mothers to avoid MSG......\n\nhttp://legacy.autism.com/medical/research/research07.htm\nBrain region-specific oxidative stress in autism: standardization of tissue protocols and evaluation of potential artifacts\nThe proposed studies will test the hypothesis that elevated oxidative stress in autism is brain-region specific. By measuring oxidative-stress markers in diverse regions of brain, we will begin the first quantitative mapping of oxidative changes in autistic brains. The hypothesis will be tested using both postmortem human brain tissue from autistic and control cases, and rat brain tissue isolated from neonates exposed to neurotoxins (LPS, MSG, and Hg) during the critical developmental period (postnatal days 4-7) corresponding to the last trimester of human pregnancy. The specific aims are: (1) to standardize tissue protocols for measuring oxidative stress markers; (2) to evaluate potential artifacts in assessing oxidative stress markers in brain tissue; and (3) to compare the region-specific distribution of oxidative-stress markers in autistic and control brains, and in animals exposed to neurotoxins known to exert oxidative effects in brain.\n\n(PI: Elizabeth Sajdel-Sulkowska, D.Sc. , Assistant Professor of Biochemistry, Dept. of Psychiatry, Harvard Medical School, Boston, Mass.)

This article is of extreme interest to me because autism appears to be rampant in my family with a number of individuals on medication and others who appear high-functioning with spectrum characteristics who are and have been dealing with those their entire lives. I am, however, a layman, not a scientist, and while some of our family believe their case is unique and not genetic, I'm afraid the numbers affected are more than enough to win an election in a landslide so I suspect genetics, particularly since these members are not even in the same geographical regions but hundreds of miles apart as far as households so environmental triggers are not the same. \n\nThe article this morning has laid a foundation I think I understand, but I may be way off in left field with my perception. As with many scientific explanations I have to build a scenario that is more easily understood at least metaphorically so I ask, if you have time, to read what I've written below and tell me if I am viewing the article's information even remotely correctly:\n\n______________________________________\nDNA is the 'bread winner' of the family. This is the one who provides the sustenance stuff to RNA the 'delegator' of the family, who sets the family structure, planning, chores and limits. \n\nIn a normal brain/body: in DNA and RNA's household, each child or family member is delegated to specific duties or chores. Each of those 'children' do only their own chore expecting and accepting that siblings will also do their specific chores. It's a team effort to keep the 'house' not just tidy, but functioning at peak performance. Because chores/duties are all different, each 'individual' can be seen also as having individual expression/creativity in the way their do their duties. \n\nIn an autistic brain DNA has given RNA the same stuff, BUT RNA rules or runs her house differently in that all children or individuals are assigned the same chores as the other. This is a family more like a military group where individuals are to follow all the same orders without being artistic or as individualized as the first. \n\nIn the first 'family' there is a higher resistance to an epidemic attack since each individual is more isolated from one another, more creative in protecting (or defense). In the second 'family' when an epidemic attacks there is less resistance or protection because they are ruled by a more singular mind and not as much in control individually.................\nso when infection attacks, this family is more likely to be overwhelmed.\n_______________________________________________\n\nI realize this is VERY simplistic, but I need to know, from someone who actually does these studies, if I am seeing this clearly or at least partly so. \n

This is an extremely interesting finding; however the obvious question that then arises is whether this brain signature differs amoung high/low functioning people with autism and also would the signature of the same person change if behavioural training improved the symptoms? In other words, how are treatments which do help at least some people, doing it?

Dear Rebecca,\n\nDNA and RNA are really sources of information, rather than "actors". Here is an analogy you and your family may find more useful:\n\nDNA is a full encyclopedia of recipes for every food made by every kind of restaurant (every protein made by every different kind of cell). But, each kind of restaurant (cell type) needs just a subset of the foods (proteins). So, a guy in the Chinese restaurant (named Mr. RNA-transcriptase) goes through the encyclopedia (DNA) and xeroxes only the Chinese recipes. Now he has a folder of all the recipes he needs to run his restaurant. And, some of these get xerox'd on wrinkled or stretched pieces of paper, so another guy, Mr. Splicosome, trims out the messy part and tapes the good recipe back together. These transcribed recipes are the messenger RNA. This is still just information. Now, he hands that folder into the kitchen (the Ribosome) and the information is translated to produce the Chinese foods, which come out of the kitchen, ready for use (in this case, the Chinese restaurant is a brain cell and the foods are proteins needed for normal brain function; whereas, the French restaurant might be a blood cell, and use a very different set of recipes from the DNA encyclopedia).\n\nThe article shows two main results:\n1) The temporal part of the brain is normally supposed to have some different recipes than the frontal part of the brain (Mandarin vs. Cantonese), but in Autistic brains, they both are more like Mandarin.\n\n2) A major problem and possible cause for mess is a problem with Mr. Splicosome doing his job. However, there are many possible root causes, still yet to be understood, that might be affecting the RNA splicing. But, it gives us a place to look for possible treatments.\n\nHope this was worthwhile "food" for thought.\n\nBaxter Zappa\n\n